1. Area of the Art
The invention relates generally to the transferrin receptor family and specifically to nucleic acid encoding transferrin receptor-like proteins, and products related thereto.
2. Description of the Prior Art
Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims. In addition, the abbreviations used are: TfR, transferrin receptor, RT-PCR, reverse transcriptase-polymerase chain reaction; Tf, transferrin; PSMA, prostate specific membrane antigen; RACE, rapid amplification of cDNA ends; G3PDH, glyceraldehyde-3-phosphate dehydrogenase; UTR, untranslated region; IRE, iron—responsive element; IRP, iron regulatory protein.
Transferrin receptor (TfR) is a key molecule involved in iron uptake by cells (1, 2). On the cell membrane the TfR homodimer binds to two diferric transferrin (Tf) molecules, resulting in internalization of the complex. In the cytoplasm, iron is released and utilized as a co-factor by several proteins, including heme, aconitase, cytochromes (3) and ribonucleotide reductase (4), or it may be stored in ferritin molecules. Since dividing cells require more iron than non-dividing cells, the expression of TfR is usually higher in rapidly dividing tissue (5), such as hematopoietic progenitor cells (6). Also, TfR expression is higher in tumor cells when compared to their normal cellular counterparts (7). The affinity of diferric Tf to TfR is modulated by HFE (8, 9).
The only other known homolog of TfR is PSMA, a human homolog of murine NAAG-peptidase (10, 11). Since the expression of PSMA is high in prostate cancer, the antibody against PSMA was approved for use as an imaging agent to detect metastasis of prostate cancer (12). The function of PSMA appears to be considerably different from that of TfR, despite the modest similarity between their extracellular domains. PSMA does not mediate endocytosis, and possesses glutamyl-carboxypeptidase activity (11, 13).
Given the importance of a transferrin receptor in an iron uptake process of cells, it is desirable to identify potential molecules which are homologous to a transferrin receptor and which perform transferrin receptor-like functions. The identification of the molecules may provide valuable tools for altering the iron uptake of specific cells. In addition, identified novel receptors may be used to identify various new ligands that have activity with other metals or other key proteins that are vital for the cells. Furthermore, since TfR expression is higher in tumor cells, the newly identified receptors may be used for diagnosing or treating tumor cells.